The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Microcirculation in the footsole as a function of mechanical pressure.

OBJECTIVE: In this study an experimental set-up for measuring skin microvascular responses of the footsole to changes in externally applied pressure was analysed. DESIGN: A clinical study. Skin microvascular blood flow was measured in healthy volunteers, during and after external mechanical pressure of different magnitudes. BACKGROUND: During standing and walking the footsole is commonly exposed to high static and dynamic mechanical pressure, resulting in changes in the microcirculation of the footsole. In diabetic patients a disturbed interaction between externally applied pressure and skin microvascular response seems to be involved in the development of a foot ulcer. METHODS: Eleven volunteers participated in the study. Static loads were applied to the heel part of the footsole with the person in a supine position. Contact pressure and skin blood flux, based on the laser Doppler technique, were simultaneously monitored. The pressure used was varied in five discrete steps between 10 and 160 kPa and applied during a period of 5 min each. The microcirculation was measured during as well as after pressure loading. RESULTS: Pressures of 40 kPa and higher do stop the blood flow in the skin microcirculation. Releasing the applied pressure resulted in a hyperaemic response. This response appears to increase in amplitude at increasing pressures up to 800% of the baseline laser Doppler fluxmetry level. Beyond a pressure level of 80 kPa the hyperaemic response seems not to be influenced by the pressure level. The time needed to achieve the maximal laser Doppler fluxmetry level decreased when the pressure was raised from 10 to 80 kPa, but increased again when higher pressures were applied (P = 0.051). An intraindividual variation of 11-50% was observed for the parameters describing the blood flux before, during, and after pressure application. CONCLUSION: Simultaneously measuring changes in contact pressure and laser Doppler flux of the footsole is a useful method to study the interaction of external mechanical pressure and skin microvascular reactions. Pressures above 40 kPa stop skin microvascular blood flow. Releasing the applied pressure results in a hyperaemic response, which increases when the applied pressure increases from 40 to 80 kPa. Higher pressures do not influence the amplitude in skin microvascular response, but result in a longer delay to maximal hyperaemia.